Correlation between Angiographic and Physiologic Evaluation of Coronary Artery Narrowings in Patients With Aortic Valve Stenosis

Correlation between Angiographic and Physiologic Evaluation of Coronary Artery Narrowings in Patients With Aortic Valve Stenosis Giuseppe Di Gioia, MDa,b, Roberto Scarsini, MDc, Teresa Strisciuglio, MDb, Chiara De Biase, MDb, Carlo Zivelonghi, MDc, Danilo Franco, MDb, Bernard De Bruyne, MD, PhDa, Flavio Ribichini, MDc, and Emanuele Barbato, MD, PhDa,b,* We aimed to assess the correlation between angiographic and physiologic evaluation of coronary lesions in aortic stenosis (AS) patients presenting with intermediate coronary stenoses at the angiography. From 2002 to 2010, we included 163 patients from 2 centers with both AS and coronary artery disease (CAD), matched by age and gender with 163 contemporary patients with CAD alone. With both quantitative coronary angiography and fractional flow reserve (FFR), we assessed 259 coronary stenoses in the AS D CAD group, and 256 in the CAD alone group. A significant correlation was found between diameter stenosis (DS) and FFR in both groups, although this was significantly stronger in the AS D CAD than in the CAD alone group (R [ L0.63 vs L0.44, p <0.01). Likewise, the correlation between minimum lumen diameter and FFR was stronger in the AS D CAD than in the CAD alone group (R [ L0.54 vs L0.41, p [ 0.05). Receiver operator characteristic curves analysis showed that DS was a better predictor of hemodynamically significant coronary stenoses (FFR £0.8) in the AS D CAD rather than in the CAD alone group (area under the curve [ 0.83 vs 0.67, p <0.01). With 50% DS cut-off value, the sensitivity, specificity, and accuracy was 77%, 66%, and 70% in the AS D CAD group versus 59%, 63%, and 61% in the CAD alone group. In both groups, the diagnostic accuracy of DS in predicting FFR was higher in the right and circumflex coronary artery compared with the left anterior descending artery (LAD), although this was only statistically significant in the AS D CAD group (area under the curve 0.88 in the right and circumflex coronary artery vs 0.76 in LAD, p [ 0.03). In conclusion, the correlation between the angiographic and hemodynamic significance of coronary stenoses is modest in AS patients. The assessment of CAD severity solely based on angiography poorly predicts the hemodynamic significance of the coronary stenosis especially when these are located in the LAD. Ó 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:106e110) Patients with aortic stenosis (AS) are present in up to 50% of the cases with associated coronary artery disease (CAD).1 In these patients, myocardial ischemia can relate to numerous factors other than epicardial stenoses such as microcirculatory impairment, left ventricular hypertrophy, and hemodynamic alterations associated with the diseased aortic valve.2e4 These factors, along with the inability in AS patients to perform a reliable noninvasive functional evaluation, portend to an assessment of the bystander CAD largely based on the sole angiographic stenosis appearance. Yet, when fractional flow reserve (FFR) guidance was adopted in AS patients, it was associated

a Department of Cardiology, Cardiovascular Research Center Aalst, Onze Lieve Vrouw (OLV) Hospital, Aalst, Belgium; bDivision of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy; and cDivision of Cardiology, Department of Medicine, School of Medicine, University of Verona, Verona, Italy. Manuscript received February 3, 2017; revised manuscript received and accepted March 30, 2017. See page 109 for disclosure information. *Corresponding author: Tel: þ(32) 53724447; fax: þ(32) 53724550. E-mail address: [email protected] (E. Barbato).

0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2017.03.250

with an overall simplification of the valve disease management and of the revascularization strategy, with no signal of adverse events up to 5 years of follow-up.5 We aimed at evaluating the relation between angiographic parameters of coronary stenosis severity as assessed by quantitative coronary angiography (QCA) and FFR in patients with AS compared with a matched group of patients with CAD alone. Methods From 2002 to 2010, we identified 163 patients from 2 centers (Cardiovascular Center, Onze Lieve Vrouw Hospital, Aalst, Belgium; University Hospital of Verona, Italy) with moderate to severe AS, in whom at least 1 coronary stenosis was evaluated both with FFR and QCA, and matched them by age and gender with 163 contemporary stable CAD patients without AS. Inclusion criteria were an aortic valve area
1.5 cm2 and/or an aortic mean gradient 25 mm Hg and stable intermediate coronary lesions (between 30% to 70% diameter stenosis [DS]). Exclusion criteria were (a) vessels with multiple lesions, grafted vessels, and bypass grafts; and (b) previous myocardial www.ajconline.org

Valvular Heart Disease/FFR Versus QCA in Aortic Stenosis

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Table 1 Clinical and angiographic characteristics Patients Men Age (years) Hypertension Dyslipidemia Diabetes Mellitus Prior myocardial infarction Prior percutaneous revascularization Prior coronary artery bypass grafting Body mass index (kg/m2) Ejection fraction Severe aortic stenosis* Vessels Vessels investigated  Left anterior descending  Right/Left circumflex Diameter stenosis Minimum lumen diameter (mm) Reference diameter (mm) Fractional flow reserve

Aortic Stenosis þ Coronary Artery Disease (n¼163)

Coronary Artery Disease alone (n¼163)

P value

100 (61%) 76 10 97 (60%) 97 (60%) 71 (44%) 12 (7%) 19 (12%) 12 (7%) 26.5  4 69.5  16.5% 137 (84%)

100 (61%) 76 10 112 (69%) 88 (54%) 40 (24%) 9 (5%) 18 (11%) 14 (9%) 26.6  5 69.9  15.1% -

1 1 0.1 0.32 < 0.01 0.65 0.86 0.83 0.83 0.85 -

(n¼259)

(n¼256)

P value

125 (48%) 134 (52%) 46  15.7% 1.6  0.6 2.9  0.6 0.85  0.09

144 (56%) 112 (44%) 47  14.1% 1.2  0.4 2.3  0.8 0.77  0.14

0.08 0.2 < 0.01 < 0.01 < 0.01

* Defined as aortic valve area
1 cm2 and/or an aortic mean gradient 40 mm Hg.

infarction in the territory of the index stenotic vessel. Severe AS was defined as an aortic valve area
1 cm2 and/ or an aortic mean gradient 40 mm Hg.6 Coronary angiography (CAG) was performed by a standard percutaneous radial or femoral approach with a 6 or 7Fr diagnostic or guiding catheter. QCA was performed by experienced technicians unaware of FFR results, as described previously.7,8 From end-diastolic still frame, reference diameter (mm), minimum luminal diameter (MLD, mm), DS (%), and lesions length were calculated. FFR was measured as previously described.9,10 Hyperemia was obtained after administration of intravenous (continuous infusion of 140 mg/kg/min) or intracoronary (bolus of at least 100 mg) adenosine. An FFR value
0.80 was considered “positive,” that is, likely to induce reversible myocardial ischemia.11e19 All analyses were performed with Prism GraphPad 5.0 (GraphPad Software Inc., CA) and SPSS 21.0 (IBM Inc., New York, NY). Descriptive statistics are reported as mean  SD or median (interquartile range); 95% confidence intervals (CIs) are added, as appropriate. Normal distribution was tested with the D’Agostino-Pearson omnibus K2 test. Correlation among variables was determined by Pearson or Spearman correlation tests and expressed as r value. Comparison between correlations was calculated using Fisher’s R to Z transformation. Sensitivity, specificity, diagnostic accuracy, and optimal diagnostic cut-off values were defined from the calculated receiver operator characteristic (ROC) curves. ROC curves were compared as described by Hanley and McNeil.20 The optimal diagnostic cut-off value was defined based on the Youden’s index, calculated as [(sensitivity þ specificity)  1], namely where the sum of sensitivity and specificity is maximized. A probability value of p <0.05 was considered statistically significant.

Results A total of 259 lesions in 163 patients were assessed in the AS þ CAD group, while 256 lesions in 163 matched patients in the CAD alone group. Clinical and angiographic characteristics are reported in Table 1. A moderate correlation was found between DS and FFR in both groups, although this was significantly better in the AS þ CAD than in the CAD alone group (R ¼ 0.63 [0.48; 0.78] vs 0.44 [0.20; 0.66], respectively; p <0.01) (Figure 1). Likewise, the correlation between MLD and FFR was better in the AS þ CAD than in the CAD alone group (R ¼ 0.54 [0.38 to 0.70] vs 0.41 [0.17 to 0.65], respectively; p ¼ 0.05). A sensitivity analysis performed in 137 patients (216 lesions) with severe AS showed overlapping results with the overall cohort of the AS þ CAD group (correlation between DS and FFR: R ¼ 0.63 [0.49 to 0.77]; correlation between MLD and FFR: R ¼ 0.54 [0.38 to 0.70]). ROC curves analysis showed that DS was a better predictor of significant coronary stenoses (FFR
0.8) in AS þ CAD rather than in the CAD alone group (area under the curve 0.83 vs 0.67, p <0.01) (Figure 2). With 50% DS cut-off value, the sensitivity, specificity, and diagnostic accuracy was 77% (95% CI 66 to 86), 66% (95% CI 60 to 74), and 70% (95% CI 64 to 75) in the AS þ CAD group versus 59% (95% CI 50 to 67), 63% (95% CI 54 to 71), and 61% (95% CI 55 to 66) in the CAD alone group, respectively. In both groups, the diagnostic accuracy of DS in predicting FFR was higher in the right and circumflex coronary artery (right/LC) compared with the left anterior descending artery (LAD), although this was only statistically significant in the AS þ CAD group (area under the curve 0.88 in right/ LC vs 0.76 in LAD, p ¼ 0.03) (Figure 3). A stratified analysis of the accuracy of 50% DS cutoff for predicting FFR <0.8 according to different lesion locations is listed in

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100

AS + CAD

100

n = 259

n = 256

80

DS (%)

DS (%)

80

CAD alone

60 40 20

60 40 20

0 0.2

0.4

0.6

0.8

1.0

FFR

0 0.2

0.4

0.6

0.8

1.0

FFR

Figure 1. Correlation between DS and FFR in patients with AS þ CAD and in patients with stable CAD alone.

100 AS + CAD AUC = 0.83

Sensitivity%

80

CAD alone AUC = 0.67

60 40 20 0

0

20

40

60

80

100

100% - Specificity% Figure 2. ROC curves analysis for the diagnostic accuracy of DS in predicting FFR <0.8 in patients with AS þ CAD and stable CAD alone. Hanley and McNeil test: p <0.01.

Table 2. The optimal cut-off values of DS in overall patients and as per vessel location are listed in Table 3. Transient atrio-ventricular block occurred in 16 (9.8%) patients in the AS þ CAD group and in 14 (8.5%) in the CAD alone group (p ¼ 0.84). No major adverse events were observed. Discussion In patients with AS, we found that (1) the correlation between angiographic stenosis severity and FFR is scattered and at the best moderate, although this is slightly but significantly better compared with patients with CAD alone; and (2) the diagnostic accuracy of the angiographic stenosis estimation is poor in case of LAD location. In stable CAD, FFR has been validated as a useful tool for clinical decision making in large randomized trials.11e13 CAG alone, in fact, is limited in predicting the physiologic significance of coronary stenoses.21,22 FFR assessment of intermediate coronary stenoses completes and complements CAG especially when noninvasive diagnostic functional evaluation is missing or inconclusive.23,24 Patients with AS have often few symptoms like some degree of exertion dyspnea, and only rarely angina. Noninvasive functional evaluation is frequently unfeasible

or inconclusive in these patients, who are often referred to CAG within the triage of the aortic valve disease. Therefore, in case of bystander coronary lesions, clinical decision making is mostly guided by the angiographic stenosis severity.2 Our findings confirm that in patients with AS only a moderate correlation exists between angiographic metrics and FFR, with marked scatter around the regression line, in keeping with patients with stable CAD. With a 50% DS cutoff value, diagnostic accuracy is only 70%, such that almost 1 of 4 lesions would be misclassified if judged only on the basis of angiography. Yet, the correlation between %DS and FFR was slightly better in patients with AS compared with patients with stable CAD alone. FFR was higher in AS patients, therefore this improved correlation was most likely because of the clustering of FFR values above 0.60 compared with CAD alone, where FFR values were spread over a broader range (Figure 1). The higher FFR values in AS patients could be explained by some selection bias: these patients were referred to CAG not strictly for angina, unlike CAD patients, but mostly for the diagnostic valvular work-up. This seems to be supported by the lower diagnostic accuracy of the 50% DS stenosis in predicting an FFR
0.80 with LAD location compared with the right/LC location of the stenosis. In fact, the larger myocardial mass (which is the case for LAD stenosis), the higher the likelihood of an anatomic-hemodynamic mismatch in the assessment of a given stenosis. Alternatively, the higher FFR values could be also explained by some degree of microvascular dysfunction, which is not infrequent in AS patients. In fact, unlike with FFR, %DS was not significantly different between AS þ CAD and CAD alone patients, suggesting that possible microcirculatory impairment could be the underlying cause of the difference in hemodynamic significance of the epicardial lesions between the 2 groups. Our study presents several limitations. First, the data were collected retrospectively over a long period of time. Moreover, we cannot exclude some selection bias, especially because the limited sample size did not allow propensity matching. Second, QCA analysis was not done by an independent core laboratory. Third, we acknowledge the higher rate of diabetes in patients with AS þ CAD compared with CAD patients. This might have further contributed to the possible difference in the degree of microvascular dysfunction between the 2 groups and

Valvular Heart Disease/FFR Versus QCA in Aortic Stenosis

AS + CAD

100

109

CAD alone

100

Right/LC

80 LAD

60

DS (%)

DS (%)

80

40

60

Right/LC LAD

40 20

20 0 0.2

0.4

0.6

FFR

0.8

0 0.2

1.0

0.4

0.6

0.8

1.0

FFR

Figure 3. Correlation between DS and FFR in lesions located in the left anterior descending artery (blue) and in the right coronary/left circumflex artery (red).

Table 2 Stratified analysis of the diagnostic accuracy of 50% diameter stenosis cutoff for predicting a fractional flow reserve value
0.80 according to different lesion locations Lesion Localization AS þ CAD - LAD - Right/LC CAD alone - LAD - Right/LC

n

Sensitivity % (95% CI)

Specificity % (95% CI)

Accuracy % (95% CI)

OR (95% CI)

p*

125 (48%) 134 (52%)

72 (58; 83) 91 (71; 99)

60 (47; 71) 71 (62; 80)

65 (57; 73) 75 (68; 82)

3.8 (1,7; 8.0) 25 (5.5; 113)

0.02

144 (56%) 112 (44%)

49 (38; 61) 73 (59; 84)

66 (52; 77) 60 (47; 72)

56 (48; 64) 66 (57; 75)

1.9 (0.9; 3.7) 4.1 (1.8; 9.1)

0.14

AS ¼ aortic stenosis; CAD ¼ coronary artery disease; LAD ¼ left anterior descending artery; LC ¼ left circumflex artery; p* ¼ p value for interaction.

Table 3 Diagnostic performance of the optimal cut-off values in the overall population and in segments with large (left anterior descending) or small (right coronary/left circumflex artery) supplied myocardial territories Lesion Localization AS þ CAD - Overall - LAD - Right/LC CAD alone - Overall - LAD - Right/LC

DS Cut-off

Sensitivity (95% CI)

Specificity (95% CI)

Accuracy (95% CI)

53.5% 40.5% 54.5%

69% (63; 75) 72% (64; 80) 91 % (86; 96)

81% (76; 86) 60% (51; 69) 71% (63; 79)

78% (73; 83) 68% (60; 76) 85% (79; 91)

50.5% 50.5% 50.5%

50% (44; 56) 50% (42; 58) 65% (56; 74)

73% (68; 78) 73% (66; 80) 70% (61; 78)

60% (54; 66) 55% (47; 63) 6 % (59;77)

AS ¼ aortic stenosis; CAD ¼ coronary artery disease; DS ¼ diameter stenosis; LAD ¼ left anterior descending artery; LC ¼ left circumflex artery.

therefore to the maximal achievable hyperemic response. Nevertheless, we performed a sensitivity analysis excluding patients with diabetes, where we found similar results in terms of sensitivity, specificity, and diagnostic accuracy with 50% DS cut-off value compared with the overall population (AS þ CAD: 75% [95% CI 61 to 85], 67% [95% CI 59 to 75], and 69% [95% CI 59 to 79]; CAD alone: 57% [95% CI 46 to 68], 67% [95% CI 55 to 78], and 62% [95% CI 53 to 71]). Fourth, we cannot investigate the impact of the hemodynamic conditions of the AS patients on the reliability of FFR. Yet, the impact of elevated central venous pressure on FFR has been shown to be negligible25, and an FFR-guided management of bystander coronary stenoses in AS patients has not been associated with higher rate of clinical end point at longterm follow-up.5

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